The final results are expected at 2am local time (10pm BST), with front-runner Mr Khan taking an early lead over Mr Sharif.
But experts believe the election could result in a hung parliament, sparking further political turmoil in in the south Asian country.
Today’s poll was marred by terrorism after a suicide bombed killed 29 people in Quetta, western Pakistan, near a polling station.
Pakistani soldiers were drafted in to guard polling stations and prevent further attacks.
The election has been a fierce battle between Imran Khan’s PTI and rival party PML-N, former led by ex-Prime Minister Nawaz Sharif.
Nawaz Sharif was ousted and jailed over corruption charges earlier this month, leaving his brother Shahbaz to fill in.
Former Pakistan cricket captain Mr Khan ran his campaign vowing to bring change to the south Asian country and tackle corruption.
This morning, he tweeted: “This is the first time in four decades the nation has a chance to defeat the entrenched status quo.”
The historic election will be only the second civilian transfer of power in Pakistan’s history.
As polls closed, Mr Khan was warned his vote could be disqualified after he cast his ballot in front of TV cameras.
Pakistan’s Election Commission claimed Mr Khan had violated Pakistan’s constitution, which guarantees the secrecy of the ballot.
Pakistani women voted for the first time in several regions, including the ultra-conservative North Waziristan.
Government administrator Mohamad Ayaz Khan hailed the breakthrough, telling reporters: “We made history today.
“It is the first time that women have come out of their homes to cast their vote.”
However, some women reported being harassed and blocked from voting in other areas including Lahore and Peshawar.
Voting is segregated throughout Pakistan, with every single polling station divided into sections for men and women.
International and domestic election observers will monitor the voting.
The EU’s Election Observation Mission has 120 monitors at polling stations in major centers across Pakistan.
A total of 342 seats on the National Assembly are up for grabs. Of these, 272 will be filled by direct elections.
The remaining seats will be distributed by proportional representation among parties gaining more than 5 percent of the vote.
Parties will need a total of 172 seats to form a government.
Additional reporting by Alahna Kindred